KR20180102559A - Biomarkers with Apillia mode for cancer treatment - Google Patents

Abstract

The present invention relates to compositions and methods, and related compositions and methods, having an Apilly mode for the treatment of cancer in individuals with cancer cells overexpressing microanatous (MiT) transcription factors.

Description

Biomarkers with Apillia mode for cancer treatment

Related patents

This application claims priority of U.S. Provisional Application No. 62 / 281,34, filed January 21, 2016, the content of which is incorporated by reference in its entirety.

Field of invention

The present invention relates to a composition and a method using the Aphelly mode in the treatment of cancer.

AplyLy mode, also referred to as STA-5326 (hereinafter " Aplyl mode "), is recognized as a potent transcriptional inhibitor of IL-12 and IL-23. For example, Wada et al. Blood 109 (2007): 1156-1164. IL-12 and IL-23 are inflammatory cytokines commonly produced by immune cells such as B-cells and macrophages in response to antigen stimulation. Other diseases characterized by autoimmune diseases and chronic inflammation are partly characterized by inadequate production of such cytokines. In immune cells, the selective inhibition of IL-12 / IL-23 transcription by apillia mode was shown to be mediated by the direct binding of apillia mode to phosphatidylinositol-3-phosphate 5-kinase (PIKyve). For example, Cai et al. Chemistry and Biol . 20 (2013): 912-921. PIKfyve plays a role in Toll-like receptor signaling, which is important in innate immunity.

Based on its activity as an immunomodulator and its activity as a specific inhibitor of IL-12 / IL-23, Aplymode has been suggested to be useful in the treatment of autoimmune and inflammatory diseases and disorders. See for example US 6,858,606 and 6,660,733 for the treatment of diseases and disorders characterized by production with IL-12 or IL-23, such as rheumatoid arthritis, sepsis, Crohn's disease, multiple sclerosis, psoriasis or insulin dependent diabetes mellitus Describes a group of pyrimidine compounds, including the aplylide mode, which is known to be useful. Similarly, Apillia mode is based on its activity to inhibit c-Rel or IL-12/23, to treat certain cancers, particularly those that are thought to play a role in promoting abnormal cell proliferation, It was proposed to be useful. See, for example, WO 2006/128129 and Baird et al., Frontiers in Oncology 3: 1 (2013, respectively).

Each of three trials in Apillia mode each focused on its potential efficacy in autoimmune and inflammatory diseases. The test was performed in patients with psoriasis, rheumatoid arthritis and Crohn's disease. An open label clinical study in psoriasis patients showed that oral administration of Apillia mode has an immunomodulatory activity that supports the inhibition of IL-12 / IL-23 synthesis for the treatment of TH1- and TH17-mediated inflammatory diseases . Wada et al., PLosOne 7: e35069 (April 2012). However, the results of a comparative study in rheumatoid arthritis and Crohn's disease did not support the notion that the inhibition of IL-12 / IL-23 by Aplymia mode is interpreted as a clinical improvement of these signs. In a randomized, double-blind, placebo-controlled phase II trial of Apillia mode in rheumatic patients, Apillia mode failed to alter synovial IL-12 and IL-23 expression. Krauz et al., Arthritis & Rheumatism 64: 1750-1755 (2012). The authors concluded, "The results do not support the notion that IL-12 / IL-23 inhibition by aplylmode may induce a firm clinical improvement in RA." Similarly, randomized, double-blind, placebo-controlled trials of Aphelly's mode for the treatment of active Crohn's disease concluded that Aphellymode was superior in resistance but did not demonstrate efficacy beyond placebo . Sands et al Inflamm Bowel Dis . 2010 Jul; 16 (7): 1209-18.

The mammalian target of rapamycin (mTOR) pathway is an important cellular signaling pathway involved in a variety of physiological functions including cell growth, cell proliferation, metabolism, protein synthesis and autophagy (La Plante et al Cell 2012 MTOR integrates intracellular and extracellular signals that signal the levels of amino acids, stress, oxygen, and energy growth factors, and regulates cellular responses to these environmental signals MTOR deregulation has been associated with a wide range of diseases and disorders, including cancer, obesity, diabetes and neurodegeneration. Certain components of the mTOR pathway have been used as drug targets to treat some of these diseases. However, therapeutic efficacy has been limited, for example, in the treatment of some cancers, and some mTOR inhibitors have been shown to have adverse effects on metabolism. Tuberous sclerosis complex The tumor suppressor genes, TSC1 and TSC2, are negative regulators of mTOR.

SUMMARY OF THE INVENTION

Apical mode has previously been shown to be a highly cytotoxic agent in TSC null cells in which the mTOR pathway is continuously activated. WO 2015/112888, the entirety of which is hereby incorporated by reference. And extended the results to show that many cancer cell lines are sensitive to aplylymode-induced cytotoxicity. B-cell lymphoma is the most sensitive to affinity mode, but this sensitivity did not show an unexpected correlation with c-Rel expression, IL-12 expression or IL-23 expression. Previous studies have been unexpected because c-Rel and / or IL-12/23 expression has suggested that the Apelli mode may be useful for cancer, which is important in promoting abnormal cell proliferation. Instead, in a further study, Apelli-mode cytotoxicity has been shown to be caused by inhibition of intracellular trafficking in the Apelli mode, which increases apoptosis. This activity was unpredictable based on the immunoregulatory activity of the affinity mode through inhibition of IL-12/23 production.

The present invention is based, in part, on the surprising discovery that the transcription factor TFEB increases the sensitivity to the Apillia mode. Since TFEB is a member of the MiT (microphthalmia) electronic human lineage, cancer that is found to have high levels of one or more MiT transcription factors is a good candidate for treating Apelli mode. Accordingly, the present invention provides a method for identifying a cancer susceptible to Aphelly mode, comprising the step of analyzing a sample of cancer cells from cancer for overexpression of one or more MiT transcripts. In one embodiment, the MiT transcript is selected from TFEB, TFE3, TFEC and MITF. In one embodiment, the MiT transcript is selected from TFEB and TFE3, or both.

In one aspect, the invention also relates to a composition for treating cancer in a subject having cancer cells that overexpress one or more MiT transcripts, a composition comprising a therapeutically effective amount of Apillia mode or a pharmaceutically acceptable salt thereof . In an embodiment, the Apilia mode is Apilly mode dimesylate. In an embodiment, the composition is in a form suitable for oral or intravenous administration. In an embodiment, the composition further comprises at least one additional active agent, which may be selected from a therapeutic or non-therapeutic agent, or a combination of therapeutic agent and non-therapeutic agent. In an embodiment, the at least one additional active agent is selected from the group consisting of a protein kinase inhibitor, a platinum based anti-neoplastic agent, a topoisomerase inhibitor, a nucleoside metabolic inhibitor, An intercalating agent, a tubulin binding agent, and combinations thereof. In embodiments, the therapeutic agent is a protein kinase inhibitor. In embodiments, the protein kinase inhibitor is pazopanib or sorafenib, or a combination thereof. The composition may further comprise a non-therapeutic agent selected to ameliorate one or more side effects of the Apical Mode. In embodiments, the non-therapeutic agent is selected from the group consisting of ondanestron, granisetron, dolsetron, and palonosetron. In an embodiment, the non-therapeutic agent is selected from the group consisting of pindolol and risperidone.

In an embodiment, the cancer being treated is refractory or metastatic to standard therapy.

In an embodiment, the cancer is selected from the group consisting of non-Hodgkins B cell lymphoma, renal cell carcinoma, melanoma, clear cell sarcoma, alveolar soft part sarcoma, or perivascular epitheloid cell tumor. In an embodiment, the cancer is kidney cancer. In an embodiment, the renal cancer is selected from the group consisting of clear cell type renal cell carcinoma, transitional cell carcinoma, Wilms tumor (nephroblastoma), renal sarcoma and benign ) Renal tumors, renal adenomas, oncocytoma, and angiomyolipomas. ≪ RTI ID = 0.0 > In an embodiment, the renal cell carcinoma is selected from the group consisting of papillary type I or type II, chromophobe of the anterior pituitary gland, hybrids, eosinophilic granulomas, translocations, angiomyocyte lipomas, oncocytic, medullary, and collecting duct carcinoma. In an embodiment, the kidney cancer comprises a TFEB translocation. In an embodiment, the TFEB translocation is t (6; 11) (p21; q12) translocation. In an embodiment, the kidney cells have mutations in the von Hippel-Lindau (VHL) gene.

In one aspect, the invention provides a method for treating cancer in a subject having cancer cells that overexpress one or more MiT transcripts, a method comprising administering to a subject a pharmaceutically effective amount of Apillia mode, or Wherein the affix mode comprises an affinity mode itself (i.e., an affinity mode free base), or a pharmaceutically acceptable salt, solvate, clathrate thereof, or a pharmaceutically acceptable salt thereof, , Hydrates, polymorphs, prodrugs, analogs or derivatives thereof. In one embodiment, the Apilia mode is either the free base of Apilia or the Apilly mode dimesylate. In an embodiment, the method further comprises a pre-treatment step of analysis of the expression of one or more MiT transcription factors in a biological sample from a subject, a biological sample containing cancer cells. MiT transcription factors can be selected from TFEB, TFE3, TFEC and MITF. In an embodiment, the MiT transcription factor is selected from TFEB or TFE3, or both.

In an embodiment, the method further comprises administering to the subject at least one additional active agent. The at least one active agent can be a therapeutic or non-therapeutic agent. The at least one additional active agent may be administered in a single dosage form with the ampicillin mode, or in a separate dosage form from the apical mode. In embodiments, the at least one additional active agent is selected from the group consisting of a kinase inhibitor, a platinum-based anti-tumor agent, a topoisomerase inhibitor, a nucleoside metabolism inhibitor, an alkylating agent, an interfering drug, a tubulin binding agent, a PD- Pathway inhibitors, and combinations thereof. In embodiments, the therapeutic agent is a protein kinase inhibitor. In embodiments, the protein kinase inhibitor is pazopanib or sorapanib, or a combination thereof. In embodiments, at least one additional active agent is selected from the group consisting of Nexavar (R), Sutent (R), Torisel (R), Afinitor (R), Avastin (R) Votrient®, Inlya®, and combinations thereof. In embodiments, the therapeutic agent is a PD-1 / PDL-1 pathway inhibitor. In an embodiment, the PD-1 / PDL-1 pathway inhibitor is selected from the group consisting of pembrolizumab (Keytruda), avelumab, atezolizumab (MPDL3280A), nivolumab (BMS-936558) Pidilizumab (CT-011), MSB0010718C and MEDI4736.

In an embodiment, the at least one active agent is a non-therapeutic agent selected to ameliorate one or more side effects of the apical mode. In an embodiment, the non-therapeutic agent is selected from the group consisting of ondansetron, granisetron, stone setron and palonosetron. In one embodiment, the non-therapeutic agent is selected from the group consisting of finsoleol and risperidone. In one embodiment, the dosage form of the apical mode composition is in an oral dosage form. In another embodiment, the dosage form of the apical mode composition is suitable for intravenous administration and administration is by a single injection or a drip bag.

In one embodiment, the subject is a human cancer patient. In one embodiment, a human cancer patient in need of treatment with apilo mode is a cancer whose cancer is refractory to standard chemo-chemotherapy. In one embodiment, a human cancer patient in need of treatment with an Aphelium mode is a patient who relapses after treatment with standard chemotherapeutic agents. In one embodiment, the cancer is kidney cancer. In one embodiment, the renal cancer is a transitional cell carcinoma, Wilms' tumor (renal cell carcinoma), renal sarcoma and benign (non-carcinoma) renal tumor, renal adenoma, eosinophilic granulomatosis and angiomyocyte lipoma. In one embodiment, the kidney cancer is a clear cell type kidney cell carcinoma.

In one embodiment, the standard chemotherapeutic treatment is selected from the group consisting of ibrutinib, rituximab, doxorubicin, prednisolone, vincristine, velcade, And one or more therapeutic agents selected from the group consisting of cyclophosphamide, dexamethasone, and éverylimus.

In one embodiment, the method is a method for treating renal cancer using a combination therapy comprising chemotherapeutic chemotherapy for the treatment of adipocyte and kidney cancer. In an embodiment, the chemo-chemotherapeutic regimen comprises a PD-1 / PDL-1 pathway inhibitor. In an embodiment, the PD-1 / PDL-1 pathway inhibitor is selected from the group consisting of peptrolliquim (MK-3475), avelelip, azezolizumab (MPDL3280A), nobiludip (BMS- 936558) ), MSB0010718C, and MEDI4736.

In another embodiment, the method is a method for treating renal cancer using a combination therapy comprising an immunotherapy for the treatment of adipocyte and kidney cancer. In one embodiment, the immunotherapy is interleukin-2 (IL-2) therapy or alpha-interferon therapy. In one embodiment, the immunotherapy comprises a PD-1 / PDL-1 pathway inhibitor. In an embodiment, the PD-1 / PDL-1 pathway inhibitor is selected from the group consisting of peptrolliquim (MK-3475), avelelip, azezolizumab (MPDL3280A), nobiludip (BMS- 936558) ), MSB0010718C, and MEDI4736.

In some embodiments, the method is a method for treating renal cancer using a combination therapy comprising a protein kinase inhibitor for the treatment of Apillia mode and kidney cancer. In one embodiment, the protein kinase inhibitor therapy is sorapenib, suminitinib, bevacizumab, lenvatinib, orveririmus.

Figure 1: Heat map representations of gene expression changes in SU-DHL-10 and WSU-DLCL2 B-NHL strains during Apelli mode treatment. Red represents an up-regulated gene, while blue represents a down-regulated gene.
Figure 2: Gene ontology analysis of commonly up-regulated genes from Figure 1 and enrichment for lysosome related genes.
Figure 3: LysoTracker staining on SU-DHL-6 and SU-DHL-10 for 24 hours and 48 hours after treatment with 200 nM (blue) affinity mode, compared to DMSO treated control (red).
Figure 4: Nuclear and cytoplasmic levels of TFEB protein in SU-DHL-6 cells treated with Apillia mode (63 nM) for 2 hours analyzed by immunoblotting.
Figure 5: Gene centric robust multi-array analysis - showing the relative TFEB mRNA levels across the tumor type (Barretina et al., 2012) extracted from CCLE with normalized mRNA expression data Box plot.
Figure 6: Stable CA46 (TFEB-deficient B-NHL) pool over-expressing GFP control or TFEB treated for 72 hours with a 10-point Apilly mode dose response.
7A: Susceptibility of different cancer cell lines to Aphelia mode in 5 day analysis.
Figure 7B: Exemplary dosing response of kidney cell line RCC-ER and normal colorectal cell line CCD841CoN to Apillia mode in a five day analysis.
Figure 8: Anti-proliferative activity of Apillia mode, as opposed to standard treatment drugs in clear cell RCC cell line (n = 5) in a five day analysis. * The value indicates the geometric mean.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compositions and methods related to the use of an affinity mode for treating an individual, preferably a human subject, in need of such treatment. The present invention relates to methods of treating cancer, which are generally characterized by overexpression of one or more MiT transcripts, such as TFEB, TFE3, TFEC and MITF, which are particularly susceptible to Aphellymode-induced cytotoxicity in the present invention ≪ / RTI > Non-limiting examples of cancers that can be characterized as overexpressing MiT transcription factors include non-Hodgkin's B cell lymphoma, kidney cell carcinoma, melanoma, clear cell sarcoma, salivary soft tissue sarcoma, . The present invention also provides a method for identifying cancer which is sensitive to Apillia mode, comprising the step of analyzing expression of one or more MiT transcription factors selected from TFEB, TFE3, TFEC and MITF.

The present invention also provides a novel therapeutic approach to cancer therapy based on combination therapy using an Apilia mode and at least one additional therapeutic agent. The combinations of therapies described in the present invention utilize the unique cytotoxic activity of Apillymode which appears to provide synergistic effects when combined with other anti-cancer agents.

As used herein, the term " affinity mode " may refer to the affinity mode itself (i.e., the affinity mode free base), or it may refer to a pharmacologically acceptable Salts, solvates, clathrates, hydrates, polymorphs, metabolites, prodrugs, analogs or derivatives thereof. The structure of the apical mode is shown in formula I:

(I)

The chemical name of the apillary mode is 2- [2-pyridin-2-yl] -ethoxy] -4-N '-( 3-methyl- benzylidene) -hydrazino] -6- (morpholin- (3-methyl-benzylidene) -hydrazino] -6- (morpholin-4-yl) -pyrimidine (IUPAC name: : (E) -4- (6- (2- (3-methylbenzylidene) hydrazinyl) -2- (2- (pyridin- 2- yl) ethoxy) pyrimidin- Yl) ethoxy) pyrimidin-4-yl) morpholine), and the CAS number is 541550-19 (E) -4- (6- (2- (3- methylbenzylidene) hydrazinyl) -2- -0.

Aplyrium modes can be prepared, for example, according to the methods described in US Patent Nos. 7,923,557 and 7,863,270, and WO 2006/128129.

As used herein, the term " pharmaceutically acceptable salt " is a salt formed from, for example, the acidic and basic groups of the aplyly mode. Exemplary salts include those derived from organic acids such as sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, But are not limited to, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, besylate, gentisinate, fumarate, gluconate, glucuronate, Benzoates, glutamates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates and pamoates (for example, 1,1'-methylene-bis- (2-hydroxy- )) Salts.

The term " pharmaceutically acceptable salts " also refers to salts prepared from an affixed mode composition having an acidic functionality, such as a carboxylic acid functional group, and a pharmaceutically acceptable inorganic or organic base.

The term " pharmaceutically acceptable salts " also refers to salts prepared from an affinity mode having a basic functionality such as an amino functional group, and a pharmaceutically acceptable inorganic or organic acid.

Salts of the compounds described in this invention can be prepared by methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Hemrich Stalil (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Can be synthesized from the parent compound by the same conventional chemical method. In general, such salts are prepared by reacting the parent compound (e.g., 2- [2-pyridin-2-yl) -ethoxy] -4-N ' Benzylidene) -hydrazino] -6- (morpholin-4-yl) -pyrimidine) with an appropriate acid.

One salt form of the compounds described herein can be converted into the free base and optionally other salt forms by methods well known to those skilled in the art. For example, the free base may be formed by passing a salt solution through a column (for example, a Strata-NH2 column) containing an amine stationary phase. Alternatively, a solution of the salt in water may be treated with sodium bicarbonate to decompose the salt and precipitate the free base. The free base can then be combined with another acid using conventional methods.

As used herein, the term " polymorph " refers to a compound of the present invention (e.g., 2- [2-pyridin-2- yl) -ethoxy] -4-N ' -Hydrazino) -hydrazino] -6- (morpholin-4-yl) -pyrimidine) or a complex thereof. Different polymorphs of the same compound exhibit different physical, chemical and / or spectroscopic properties. The different physical properties include stability (for example, for heat or light), compressibility and density (which are important in formulation and product manufacture), and dissolution rate (which may affect bioavailability) But is not limited to. Differences in stability include chemical reactivity (e.g., differential oxidation, such as a more rapid discoloration of the dosage form when the polymorph is composed of one polymorph rather than another polymorph), or mechanical properties For example, one polymorphic pellet is more susceptible to destruction at high humidity (e.g., the pellet is broken on storage as the kinematically preferred polymorph is converted to a thermodynamically more stable polymorph), or both ). ≪ / RTI > The different physical properties of the polymorph may affect their process. For example, one polymorph may be more easily solvated, or it may be more difficult to filter or wash away impurities than another due to, for example, the shape or size distribution of the particles.

As used herein, the term " hydrate " refers to a compound of the invention (such as, for example, 2- [ Pyridin-2-yl) -ethoxy] -4-N '- (3-methyl- benzylidene) -hydrazino] -6- do.

As used herein, the term " clitorite " refers to a particle (e.g., a channel) in the form of a crystal lattice comprising a space 4-N '-( 3-methyl-benzylidene) -hydrazino] -6- (morpholin- Yl) -pyrimidine) or a salt thereof.

As used herein, the term " prodrug " refers to any of those described in the present invention, which can be hydrolyzed, oxidized or otherwise reacted under biological conditions (in vitro or in vivo) - (3-methyl-benzylidene) -hydrazino] -6- (morpholin-4-yl) - pyrimidine). ≪ / RTI > Prodrugs may be activated only through such reactions under biological conditions, or they may have activity in their unreacted form. Examples of prodrugs contemplated in the present invention are biodegradable misters such as biodegradable amides, biodegradable esters, biodegradable carbamates, biodegradable carbonates, biodegradable ureas and biohydrolyzable phosphate analogs. 4-N '-( 3-methyl-benzylidene) -hydrazino] -6 (2-pyridin-2-yl) - (morpholin-4-yl) -pyrimidines), but are not limited thereto. Other examples of prodrugs include derivatives of any of the compounds of formula according to the invention comprising a -NO, -NO _2, -ONO, or -ONO ₂ moieties. Prodrugs can generally be prepared using well-known methods, such as those described by Burger's Medicinal Chemistry and Drug Discovery (1995) 172-178, 949-982 (Manfred E. Wolff ed., 5th ed) have.

As used herein, the term " solvate " or " pharmaceutically acceptable solvate " refers to any of the compounds described in the present invention (e.g., 2- [ (Morpholin-4-yl) -pyrimidine) in the presence of a base such as triethylamine or triethylamine. The term solvate includes a hydrate (e.g., a semi-hydrate, a 1-hydrate, a 2-hydrate, a 3-hydrate, a 4-hydrate, etc.).

As used herein, the term " analogue " is structurally similar to another, but is intended to encompass a composition (replacement of a nuclear element of another element of one atom or the presence of a particular functional group or replacement of one functional group with another functional group) ≪ / RTI > refers to a compound having a slight difference in its activity. Thus, analogs are compounds that are similar or comparable in function and appearance to reference compounds, but not in structure or in origin. As used herein, the term " derivative " refers to a compound having a common core structure and being substituted by various groups as described herein.

Methods of treatment and diagnosis

The present invention provides a method for the treatment of cancer in an individual having cancer cells that overexpress the ocular microtia (MiT) transcription factor. In an embodiment, the method comprises administering to a subject a therapeutically effective amount of an affilient mode or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, prodrug, analog or derivative thereof do. In an embodiment, the cancer overexpresses an MiT transcription factor selected from TFEB, TFE3, TFEC and MITF. In an embodiment, the MiT transcription factor is selected from TFEB and TFE3, or both.

In an embodiment, the invention also provides a diagnostic method for identifying cancer that is vulnerable to Aphellymode therapy, the method comprising administering to the patient one or more compounds of the invention, wherein the overexpression of one or more MiT transcription factors indicates that the cancer is vulnerable to Aphelly mode And analyzing a sample of cancer for expression of the MiT transcript.

In embodiments, the cancer is selected from the group consisting of brain cancer, glioma, sarcoma, breast cancer, lung cancer, non-small-cell lung cancer, mesothelioma, appendiceal cancer, genitourinary cancers, , Gastrointestinal cancer, hepatocellular carcinoma, gallbladder cancer, esophagus cancer, ovarian cancer, renal cell carcinoma, prostate cancer, bladder cancer, testicular cancer, penile cancer, cervical cancer, ovarian cancer, von Hippel- Lindows disease, head and neck cancer, , Stomach cancer, colon cancer, pancreatic cancer, neuroendocrine tumors, thyroid tumor, submucosal tumor, adrenal tumor, hematological malignancy or leukemia.

In an embodiment, the cancer is a kidney cancer having a TFE3 translocation, a soft tissue sarcoma, or a perivascular epitheloid cell neoplasm.

In embodiments, the cancer is kidney cancer, colon cancer, endometrial cancer, or stomach cancer having an FLCN inactive mutation.

In one embodiment, the kidney cancer is kidney cell carcinoma (RCC). In one embodiment, the renal cell carcinoma is selected from the group consisting of clear cell type renal cell carcinoma, papillary renal cell carcinoma, non-dysplastic cell type renal cell carcinoma of the anterior pituitary, other rare types of renal cell carcinoma (e. G. Selected from the group consisting of multilocular cystic RCC, watery carcinoma, mucinous tubular and spindle cell carcinoma, neuroblastoma-associated RCC, unclassified renal cell carcinoma) and metastatic RCC do. In one embodiment, the kidney cancer is selected from the group consisting of a transitional cell carcinoma, a Wilms tumor (renaloblastoma), a renal sarcoma and a benign (non-carcinoma) renal tumor, a renal adenoma, an acidic granulomatous tumor, and a vascular muscle lipoma . In an embodiment, the RCC is a subtype selected from papillary type I or type II, non-staining cells of the anterior pituitary gland, hybrids, eosinophilic granulomas, translocations, angiomyocyte lipomas, tumor cells, water quality and collecting neoplasia.

In one embodiment, the cancer is lymphoma. In one embodiment, the lymphoma is a B cell lymphoma. In one embodiment, the B cell lymphoma is selected from the group consisting of Hodgkin's B cell lymphoma and non-Hodgkin's B cell lymphoma. In one embodiment, the B cell lymphoma is selected from the group consisting of DLBCL, follicular lymphoma, marginal zone lymphoma (MZL) or mucosa associated lymphatic tissue lymphoma (MALT), small lymphocytic lymphoma is a non-Hodgkin's B cell lymphoma selected from the group consisting of small cell lymphocytic lymphoma (overlapping with chronic lymphocytic leukemia) and mantle cell lymphoma. In one embodiment, the B cell lymphoma is selected from Burkitt's lymphoma, primary mediastinal (thymic) large B-cell lymphoma, Waldenstrøm macroglobulinemia Lymphocytic lymphoma, lymph node, lymph node, lymph node, lymph node, lymph node, lymph node, lymph node, lymph node, lymph node, lymph node, lymph node, lymph node, (T-cell / histiocyte-rich large B-cell lymphoma), T-cell / histiocyte-rich large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, , Primary central nervous system lymphoma, primary cutaneous diffuse large B-cell lymphoma, leg type ), EBV-positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma associated with inflammation, intravascular macroscopic B-cell lymphoma, Cell lymphoma, an ALK-positive large B-cell lymphoma, and a Plasmablastic lymphoma.

In one embodiment, the cancer is a melanoma. Melanoma is a type of skin cancer found in the epidermis of the skin, which is formed from melanocytes (pigment-containing cells in the skin). The epidermis is the upper or outer layer of the two major layers that make up the skin of the cell and is separated from the deeper layers of skin by the basement membrane. Skin cancer, such as melanoma, progresses through the epidermis and grows into a deeper layer of skin through the membrane, in order to access the blood supply so that the tumor can become metastasized.

There are four basic types of melanomas. Three of them start on the spot - they only occupy the upper layers of the skin, sometimes invasive; The fourth case is intrusive from the beginning. Invasive melanomas are more severe because they penetrate deeper into the skin and can spread to other parts of the body.

The superficial spreading melanoma is the most common type, accounting for about 70 percent of the total. This is most commonly found in young people. As the name suggests, these melanomas grow along the upper layers of the skin for a fairly long time before penetrating deeper.

The black dotted melanoma (Lentgo maligna) stays close to the surface of the skin for a long time and appears as a generally flattened or slightly elevated mottled tan, brown or dark brown discoloration, similar to the superficial spreading type Do. This type of in situ melanoma is most commonly found in elderly people, is chronically sun-exposed, and results from skin damage on the face, ears, arms, and upper trunk. When such a cancer becomes permeable, it is referred to as a black point melanoma.

Acral lentiginous melanoma also superficially spreads before penetrating deeper. However, this is quite different from others in that it usually appears as a black or brown discoloration under the nails or on the soles or palms of the hands. This type of melanoma is often found in dark-skinned people and can develop more rapidly than superficially spreading melanoma and black dot melanoma. This is the most common black species for African Americans and Asians, and is the least common among white people.

Nodular melanoma is generally invasive when first diagnosed. Malignant tumors are recognized when they become bumps. It is generally black, but sometimes blue, gray, white, brown, tan, red or skin color.

In one embodiment, the cancer is a colon cancer. Colon cancer (also known as colon cancer, rectal cancer or bowel cancer) is the development of cancer in the colon or rectum. Colon cancer was staged according to the TNM staging system. The TNM staging system is one of the most widely used in cancer system, and has been applied by UCC (Union for International Cancer Control) and AJCC (American Joint Committee on Cancer). The TNM system is a secondary tumor that is formed due to the spread of the size and / or extent (T) of the primary tumor, the amount spreading near the lymph node (N) and the presence of metastasis (M) . A number is added to each letter indicating the size and / or degree of primary tumor and the degree of cancer spread.

The present invention also provides a method comprising a combination therapy for the treatment of cancer. As used herein, " co-therapy " or " co-therapy " refers to the administration of an agent that is part of a particular therapy intended to provide beneficial effects from the affinity mode and the co- And a pharmacologically effective amount of the pill mode. The at least one additional agent may be a therapeutic or non-therapeutic agent. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-action due to the combination of therapeutic compounds. The beneficial effect of co-administration may also relate to the alleviation of toxicity, side effects or adverse effects associated with other agents in combination. &Quot; Combination therapy " is not intended to include the administration of two or more therapeutic compounds, as part of a separate monotherapy regimen, incidentally and arbitrarily obtaining an intended or unexpected beneficial effect.

The at least one additional active agent can be a therapeutic agent, for example, an anti-cancer or cancer chemotherapeutic agent, or a non-therapeutic agent, and combinations thereof. With respect to therapeutic agents, the beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-action due to the combined use of pharmaceutically active compounds. With respect to the non-therapeutic agent, the beneficial effect of the combined use may be with regard to alleviation of the toxicity, side effects, adverse effects associated with the pharmaceutically active agent in combination.

In one embodiment, the at least one additional agent is a non-therapeutic agent that alleviates one or more side effects selected from one or more side effects of the Apical Mode composition, nausea, vomiting, headache, dizziness, mild dizziness, drowsiness and stress. In one aspect of this embodiment, the non-therapeutic agent is an antagonist of a serotonin receptor, also known as a 5-hydroxytryptamine receptor or a 5-HT receptor. In one aspect, the non-therapeutic agent is an antagonist of the 5-HT3 or 5-HT1a receptor. In one aspect, the non-therapeutic agent is selected from the group consisting of ondansetron, granisetron, dolassitron and palanosetron. In yet another aspect, the non-therapeutic agent is selected from the group consisting of finolol and risperidone.

In an embodiment, the at least one additional agent is a therapeutic agent. In one aspect, the therapeutic agent is an anti-cancer agent described in more detail below.

In the context of the combination therapies, the administration of the Aphellymode or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog or derivative thereof is administered concurrently with the administration of one or more additional active agents Or sequential. In another embodiment, administration of the different components of the combination therapy may be of different frequencies. One or more additional agents may be formulated prior to administration of the compounds of the invention (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 (For example, 5 minutes, 15 minutes, 30 minutes) at the time of administration, or at the time of administration (e.g., 5 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, , 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks Or after 12 weeks).

One or more additional active agents may be made for co-administration with an affix mode in a single dosage form, as described in more detail herein. One or more additional active agents may be administered separately from the dosage form comprising the ampicillin mode. If the additional active agent is administered separately from the epileptic mode, it may be the same or a different route of administration than the epileptic mode.

Preferably, administration of a composition comprising an affixed mode in combination with one or more additional active agents provides a synergistic response in the treated subject. In this context, the term " synergy " refers to the efficacy of a combination that is more effective than the additional effect of a single treatment alone. The synergistic effect of the combination therapy according to the present invention may allow the use of less dosage and / or less frequency of at least one agent in combination, as compared to dosages and / or frequencies other than combination. An additional beneficial effect of the combination may lead to avoidance or reduction of negative or unwanted side effects associated with the use of the therapy in combination alone (also referred to as monotherapy).

&Quot; Combination therapy " also encompasses administration of a compound of the invention in additional combination with non-drug therapy (e. G., Surgery or radiation therapy). Where the combination therapy further comprises a non-drug therapy, the non-drug therapy may be performed at any appropriate time, so long as the beneficial effect is achieved by the co-action of the combination of the therapeutic compound and the non- have. For example, where appropriate, when the non-drug therapy is temporarily removed from the administration of the therapeutic compound, beneficial effects are still achieved, perhaps for several days or even weeks.

Non-drug therapies include, but are not limited to, chemotherapeutic chemotherapy, radiotherapy, hormone therapy, anti-estrogen therapy, gene therapy, surgery (eg radical nephrectomy, partial nephrectomy, laparoscopic robotic surgery laparoscopic and robotic surgery), radiofrequency ablation and cryoablation. For example, non-drug therapy may be used to remove ovaries (e.g., to reduce body estrogen levels), thoracentesis (e.g., to remove fluid from the chest), paracentesis, (For example, to remove fluid from the abdomen), surgery to remove or contract vascular muscle lipomas, lung transplantation (and optionally with antibiotics to prevent transplant-induced infections) or oxygen therapy (e.g., Through a nasal cannula containing two small plastic tubes or prongs located in both nostrils, through a facial mask that fits the nose and mouth, or by transtracheal oxygen therapy Called through a small tube that is inserted into the organ through the anterior portion of the neck).

In one embodiment, the at least one additional agent is an agent that alleviates one or more side effects of the Aphelly mode selected from nausea, vomiting, headache, dizziness, mild dizziness, drowsiness and stress. In one aspect of this embodiment, the additional agent is an antagonist of a serotonin receptor, also known as a 5-hydroxytryptamine receptor or a 5-HT receptor. In one aspect, the additional agent is an antagonist of the 5-HT ₃ or 5-HT _1a receptor. In one aspect, the agent is selected from the group consisting of ondansetron, granisetron, dolacetron and palanosetron. In another aspect, the agent is selected from the group consisting of finsoleol and risperidone.

In an embodiment, the at least one additional agent is an anti-cancer agent. In embodiments, when the cancer is renal cancer, the anti-cancer agent is selected from the group consisting of VEGF inhibitors such as sunitinic, pazopanib, bevacizumab, sorafenib, carbozanthinib and axitinib, or Ebelorimus or Temsirolimus Can be selected from the same mTOR inhibitor.

In one aspect, the anti-cancer agent is selected from taxol, vincristine, doxorubicin, temsirolimus, carboplatin, opapumem, rituximab and combinations thereof.

In one embodiment, the at least one additional agent is selected from the group consisting of chlorambucil, ipospamide, doxorubicin, mesalamine, thalidomide, lenalidomide, temsirolimus, eberorimus, fludarabine, Docetaxel, docetaxel, docetaxel, oppartum, rituximab, dexamethasone, prednisone, CAL-101, ibriottumone, tositumomab, bothezomib, pentostatin, endostatin or a combination thereof.

In one embodiment, the at least one additional agent is selected from the group consisting of Afinitor (Everolimus), Aldesleukin, Avastin (bevacizumab), Axitinib, Bebacizumab, (Aldose leucine), Inlyta (acity nip), interleukin-2 (aldes leucine), Nexavar (sorapeniptosylate), pazopanib, hydrochloride, pro The present invention relates to a method for the treatment and prophylaxis of a disease or condition selected from the group consisting of Proleukin (Aldese leukin), Sorapenib tosylate, Sunitinib Malate, Sutent (Sutent) (Sunitinib Malate), Temsirolimus, Torisel Votrient (pazopanib hydrochloride), or a combination thereof.

In one embodiment, at least one additional agent is directed to a targeted therapy targeting a tissue environment that contributes to cancer specific gene, protein or cancer growth and survival. This type of therapy inhibits the growth and spread of cancer cells, limiting damage to healthy cells.

In one embodiment, at least one additional agent is intended for anti-angiogenic therapy that focuses on stopping angiogenesis, a process of making new blood vessels. Because tumors require nutrients that are delivered by blood vessels to grow and spread, the goal of anti-angiogenesis therapy is to "starve" the tumor. One anti-angiogenic drug, bevacizumab (Avastin), has been shown to slow the growth of tumors in people with metastatic renal carcinoma. Bevacizumab in combination with interferon delays tumor growth and spreading.

In one embodiment, at least one additional agent is directed to an immunotherapy, also referred to as a biological therapy, designed to enhance the natural defense of the body to fight cancer. It uses materials made to improve, target, or restore immune system function in the body or in the laboratory. For example, interleukin-2 (IL-2) is a drug that has been used to treat kidney cancer as well as AM0010 and interleukin-15. These are hormones of cells called cytokines produced by leukocytes and are important for the function of the immune system, including the destruction of tumor cells. Alpha-interferon is another type of immunotherapy used to treat spreading kidney cancers. Interferon appears to alter the protein on the surface of cancer cells and slow their growth. Many combined therapies of IL-2 and alpha-interferon in combination with chemotherapy for advanced renal cancer patients are more effective than IL-2 or interferon alone.

In an embodiment, at least one additional agent is a PD-1 / PDL-1 pathway inhibitor. In embodiments, the PD-1 / PDL-1 pathway inhibitor may be selected from the group consisting of: Pep rrolei jeweit (Keytruda), Abelux, Azeolizumab (MPDL3280A), Nibuloharum (BMS-936558), Pidilizumab (CT-011), MSB0010718C MEDI4736.

In an embodiment, at least one additional agent is a checkpoint inhibitor. Therapeutics using these compounds act by targeting molecules that play a role in checking and balancing the immune response. By inhibiting such inhibitory molecules or, alternatively, activating stimulatory molecules, such therapies are designed to trigger or enhance existing anti-cancer immune responses. In an embodiment, the checkpoint inhibitor is selected from the group consisting of PD-1, anti-CD27, B7-H3, KIR, LAG-3, 4-1BB / CD137, GITR, Keytruda, PD- LIL-3 antibody), BAL-Ll-3 antibody), BAL-Ll antibody (anti-Ll antibody), vallumab (CDX-1127, anti-CD27 antibody), MGA217 (antibody targeting B7-H3), lirilumab CD40 (antibody), TRX518 (GITR antibody) and MK-4166 (GITR antibody), anti-TIM3 antibody (anti-TIM3 antibody) ). ≪ / RTI >

In an embodiment, the at least one additional agent is an anti-cancer vaccine designed to induce an immune response against a tumor-specific or tumor-associated antigen, which promotes the immune system to attack cancer cells with such an antigen. In an embodiment, the anti-cancer vaccine may be selected from AGS-003, DCVax and NY-ESO-1.

In an embodiment, at least one additional agent is an immunostimulant, such as a recombinant protein, used to activate the immune system to attack cancer cells. In an embodiment, the immunostimulant is denenicokin (recombinant IL-21).

In an embodiment, at least one additional agent is a small molecule that modulates the immune system to facilitate the removal of cancer cells. In embodiments, the small molecule may be selected from epacadostat (IDO inhibitor) and PLX3397 (inhibitor of CSF-1R).

In embodiments, at least one additional agent is genetically modified or chemically treated to increase the activity of the immune cell, and then reintroduced into the patient for the purpose of ameliorating the anti-cancer response of the immune system. Lt; RTI ID = 0.0 > immune < / RTI >

In the context of the methods described herein, the amount of affixed mode administered to an individual is a therapeutically effective amount. The term " therapeutically effective amount " means an amount sufficient to treat and alleviate the symptoms of the disease or disorder being treated, to decrease the severity or duration, or to increase or improve the therapeutic effect of another therapy, Quot; refers to an amount sufficient to exhibit a therapeutic effect to be detected. In one embodiment, the therapeutically effective amount of the apical mode composition is an amount effective to inhibit PIKfyve kinase activity.

An effective amount of the Apillia mode is about 0.001 mg / kg to about 1000 mg / kg, about 0.01 mg / kg to 100 mg / kg, about 10 mg / kg to 250 mg / ; Or the lower limit of the range is between 0.001 mg / kg and 900 mg / kg and the upper limit of the range is between 0.1 mg / kg and 1000 mg / kg (e.g. 0.005 mg / kg and 200 mg / kg, 0.5 mg / kg and 20 mg / kg). Effective doses will also vary according to the likelihood of co-use with other therapeutic therapies, such as the condition being treated, the route of administration, the use of the excipient and the use of other agents, as will be appreciated by those skilled in the art. See U.S. Patent No. 7,863,270, which is incorporated herein by reference.

In a more specific aspect, the Aphelly mode may be used for at least one week (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 36, 48, (For example, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225 , 250, 275, or 300 mg / day). Preferably, the Apicaly mode is administered in a dose of 100-1000 mg / day for 4 weeks or 16 weeks. Alternatively or in addition, the Apillia mode is administered in doses of 100-300 mg twice daily for 8 weeks or alternatively for 52 weeks. Alternatively or in addition, the ampicillin mode composition is administered in doses of 50 mg to 1000 mg twice daily for 8 weeks or alternatively for 52 weeks.

An effective amount of the Apicalmode composition can be administered once a day, twice to five times a day, up to twice a day or up to three times a day, or up to eight times a day. In one embodiment, the Aphellymode composition is administered three times daily, twice daily, once a day for 14 days in a 3-week cycle (four times daily, three times daily or twice daily Or once a day), taking 7 days for up to 5 days or 7 days in a 3 week cycle (4 times a day, 3 times a day, twice a day, or once a day) 16 days, or once every two days, or once a week, or once every two weeks, once every three weeks.

According to the methods described in the present invention, the "subject in need" is an individual who has had kidney cancer, or an individual with an increased risk of developing kidney cancer compared to the majority of the population. The individual in need may be an entity that is " non-responsive " or " refractory " to the currently available therapy for cancer. In this context, the terms " non-responsive " and " refractory " refer to a response of an individual to a treatment that is clinically insufficient to alleviate one or more symptoms associated with the disease or disease. In one aspect of the methods described herein, the individual in need is a cancer that is refractory to standard therapy or recurring after standard therapy.

"Entity" includes mammals. The mammal may be, for example, any mammal, such as a human, a primate, a vertebrate, a bird, a mouse, a rat, a poultry, a dog, a cat, a cow, a horses, a goat, a camel, Preferably, the mammal is a human. The term " patient " refers to a human individual.

The present invention also provides a single treatment for the treatment of renal cancer described herein. As described herein, " monotherapy " refers to the administration of an active or therapeutic compound to a subject in need.

As used herein, " treatment ", " treating " or " treatment " describes the management and care of a patient for the purpose of fighting a disease, condition, or disease, , Or the administration of an affliple mode to remove the disease, condition or disease.

As used herein, the terms " prophylaxis ", " preventing " or " prophylaxis " describe reducing or eliminating the onset of a symptom or complication of a disease, condition or disease, ≪ RTI ID = 0.0 > and / or < / RTI >

In one embodiment, the administration of the Aphelium mode leads to the elimination of symptoms or complications of the cancer being treated, but the removal of the cancer is not required. In one embodiment, the severity of the symptoms is reduced. In the context of cancer, these symptoms include the degree to which the tumor secretes growth factors, the degree to which the extracellular matrix degrades, the degree of vessel development, the degree of loss of adhesion to juxtaposed tissues or the number of metastases, Including clinical markers of severity or progress, including the extent to which the disease progresses.

Treating cancer in accordance with the methods described herein can reduce tumor size. A decrease in the size of the tumor may also be referred to as " tumor regression ". Preferably, after treatment, the tumor size is greater than or equal to 5% compared to the size before treatment; More preferably 10% or more; More preferably 20% or more; More preferably 30% or more; More preferably 40% or more; , Even more preferably at least 50%; Most preferably at least 75%. The size of the tumor can be measured by any reproducible instrument of measurement. The size of the tumor can be measured by the diameter of the tumor.

Treating cancer in accordance with the methods described herein can reduce tumor volume. Preferably, after treatment, the tumor volume is greater than or equal to 5%, as compared to the size before treatment; More preferably 10% or more; More preferably 20% or more; More preferably 30% or more; More preferably 40% or more; , Even more preferably at least 50%; Most preferably at least 75%. Tumor volume can be measured by any reproducible tool of measurement.

Treating cancer in accordance with the methods described herein can reduce the number of tumors. Preferably, after treatment, the number of tumors is greater than or equal to 5%; More preferably 10% or more; More preferably 20% or more; More preferably 30% or more; More preferably 40% or more; , Even more preferably at least 50%; Most preferably at least 75%. The number of tumors can be measured by any reproducible instrument of measurement. The number of tumors can be measured visually or by counting tumors seen at a specific magnification. Preferably, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

Treating cancer in accordance with the methods described herein can reduce the number of metastatic lesions in other tissues or organs far from the primary tumor site. Preferably, after treatment, the number of metastatic lesions is greater than or equal to 5% compared to the number before treatment; More preferably 10% or more; More preferably 20% or more; More preferably 30% or more; More preferably 40% or more; , Even more preferably at least 50%; Most preferably at least 75%. The number of metastatic lesions can be measured by any reproducible tool of measurement. The number of metastatic lesions can be measured visually or by calculating metastatic lesions at specific magnification. Preferably, the specific magnification is 2x, 3x, 4x, 5x, 10x, or 50x.

Treating cancer in accordance with the methods described herein can increase the average survival time of a population of treated individuals compared to a population receiving only the carrier. Preferably, the average survival time is 30 days or more; More preferably 60 days or more; More preferably at least 90 days; Most preferably at least 120 days. An increase in the average survival time of a population can be measured by any reproducible tool. For example, an increase in the average survival time of a population can be measured by calculating the average length of survival after initiating treatment with the active compound for the population. For example, an increase in the average survival time of a population may also be measured by calculating the average length of survival after completing one round of treatment with the active compound for the population.

Treating cancer in accordance with the methods described herein can increase the average survival time of a population of treated individuals compared to a population of untreated individuals. Preferably, the average survival time is 30 days or more; More preferably 60 days or more; More preferably at least 90 days; Most preferably at least 120 days. An increase in the average survival time of a population can be measured by any reproducible tool. For example, an increase in the average survival time of a population can be measured by calculating the average length of survival after initiation of treatment with the active compound for the population. For example, an increase in the average survival time of a population can also be measured by calculating the average length of survival after completing one round of treatment with the active compound for the population.

Treating cancer in accordance with the methods described herein can increase the average survival time of a population of treated individuals compared to a population that received a single treatment with a drug that is not an amphiliac mode. Preferably, the average survival time is 30 days or more; More preferably 60 days or more; More preferably at least 90 days; Most preferably at least 120 days. An increase in the average survival time of a population can be measured by any reproducible tool. For example, an increase in the average survival time of a population can be measured by calculating the average length of survival after initiation of treatment with the active compound for the population. For example, an increase in the average survival time of a population can also be measured by calculating the average length of survival after completing one round of treatment with the active compound for the population.

Treating cancer in accordance with the methods described herein can reduce the mortality rate of a population of treated individuals compared to a population receiving only the carrier. Treatment of a disease, disorder or condition according to the methods described herein may reduce the mortality of a population of treated individuals compared to the untreated population. Treatment of a disease, disorder or condition according to the methods described herein can reduce the mortality of a population of treated individuals compared to a population receiving a single treatment with a drug that is not an amphilia mode. Preferably, the mortality is at least 2%; More preferably 5% or more; More preferably 10% or more; Most preferably at least 25%. The reduction in mortality of a population of treated individuals can be measured by any reproducible tool. For example, a reduction in the mortality rate of a population can be determined by calculating the average number of disease-related deaths per unit time after initiation of treatment with the active compound for the population. For example, a reduction in the mortality rate of a population can also be measured by calculating the average number of disease-related deaths per unit time after completion of one round of treatment with the active compound for the population.

Treating cancer in accordance with the methods described herein can reduce tumor growth rates. Preferably, the tumor growth rate after treatment is at least 5% as compared to before treatment; More preferably at least 10%; More preferably at least 20%; More preferably at least 30%; More preferably at least 40%; More preferably at least 50%; Even more preferably at least 50%; Most preferably at least 75%. The tumor growth rate can be measured by any reproducible tool of measurement. The tumor growth rate can be measured according to the change in tumor diameter per unit time. In one embodiment, the tumor growth rate after treatment may be about 0, and is measured to remain the same, e.g., the tumor has stopped growing.

Treating cancer in accordance with the methods described herein can reduce tumor regrowth. Preferably, after treatment, the tumor regrowth is less than 5%; More preferably less than 10%; More preferably less than 20%; More preferably less than 30%; More preferably less than 40%; More preferably less than 50%; , Even more preferably less than 50%; Most preferably less than 75%. Tumor regrowth can be measured by any reproducible tool of measurement. For example, tumor regrowth is measured by measuring the increase in tumor diameter after tumor shrinkage after treatment. The reduction in tumor regrowth is attributed to the tumor not recurring after therapy has been discontinued.

Treatment or prevention of a cell proliferative disorder according to the method described in the present invention can reduce the cell proliferation rate. Preferably, after treatment, the cell proliferation rate is at least 5%, more preferably at least 10%; More preferably at least 20%; More preferably at least 30%; More preferably at least 40%; More preferably at least 50%; Even more preferably at least 50%; Most preferably at least 75%. The cell proliferation rate can be measured by any reproducible instrument of measurement. For example, cell proliferation is measured by measuring the number of cells that divide in a tissue sample per unit time.

Treatment or prevention of cell proliferative diseases according to the method described in the present invention can reduce the proportion of proliferating cells. Preferably, after treatment, the proportion of proliferating cells is at least 5%; More preferably at least 10%; More preferably at least 20%; More preferably at least 30%; More preferably at least 40%; More preferably at least 50%; Even more preferably at least 50%; Most preferably at least 75%. The proportion of proliferating cells can be measured by any reproducible tool of measurement. Preferably, for example, the proportion of proliferating cells is determined by quantifying the number of dividing cells compared to the number of non-dividing cells in a tissue sample. The proportion of proliferating cells can be equivalent to the mitotic index.

Treatment or prevention of a cell proliferative disease according to the method described in the present invention can reduce the size of a part or zone of cell proliferation. Preferably, after treatment, the portion or zone of cell proliferation is at least 5%; More preferably at least 10%; More preferably at least 20%; More preferably at least 30%; More preferably at least 40%; More preferably at least 50%; Even more preferably at least 50%; Most preferably at least 75%. The size of the part or zone of cell proliferation can be measured by any reproducible instrument of measurement. The size of the part or zone of cell proliferation can be measured as the diameter or width of the part or zone of cell proliferation.

Treatment or prevention of a cell proliferative disease according to the method described in the present invention can reduce the number or proportion of cells having an abnormal appearance or morphology. Preferably, after treatment, the number of cells having an abnormal morphology is at least 5% compared to before treatment; More preferably at least 10%; More preferably at least 20%; More preferably at least 30%; More preferably at least 40%; More preferably at least 50%; Even more preferably at least 50%; Most preferably at least 75%. Abnormal cell morphology can be measured using a microscope, for example, an inverted tissue culture microscope. Abnormal cell morphology may appear in the form of nuclear pleiomorphism.

As used herein, the term " selectively " means that it tends to occur at a higher frequency in one population than in another population. The group to be compared can be a cell group. Preferably, the Apilian mode selectively acts on over-proliferating cells or abnormally proliferating cells as compared to normal cells. As used herein, "normal cell" is a cell that can not be classified as part of a "cell proliferative disease". Normal cells do not have uncontrolled or abnormal growth, or both, that cause unwanted conditions or diseases. Preferably, normal cells have a functioning cell cycle checkpoint regulation mechanism that functions normally. Preferably, the affinity mode modulates one molecular target (e. G., The target kinase), while the other molecular target (e. G., Non-target kinase) acts selectively to not regulate significantly. The present invention also provides a method for selectively inhibiting the activity of an enzyme such as kinase. Preferably, when two or more occurrences occur more frequently in group A than in group B, events occur selectively in group A as compared to group B. If it occurs more than 5 times more frequently in group A, the event occurs selectively. 10 times more in group A compared to group B; More preferably 50 times or more; Still more preferably 100 times or more; Most preferably, more than 1000 times more frequently, events occur selectively. For example, if apoptosis occurs more frequently than 2 times in pathologic or over - proliferating cells compared to normal cells, apoptosis may be selected selectively in pathologic or over - proliferating cells.

Pharmaceutical compositions and formulations

The present invention provides a pharmaceutical composition comprising at least one pharmaceutically acceptable salt or solvate thereof, comprising an amount of Apillia mode or a pharmaceutically acceptable salt, solvate, clathrate, hydrate, polymorph, metabolite, prodrug, analog or derivative thereof Wherein the amount is an amount effective to inhibit an amount and / or PIKfyve effective for the treatment of cancer as described herein in a cancer cell of an individual afflicted with cancer.

In one embodiment, the Apicaly mode is an Apicaly mode free base. In one embodiment, the apical mode is apical mode dimesylate.

In one embodiment, the Apillia mode is combined with at least one additional reagent in a single dosage form. In one embodiment, the composition further comprises an antioxidant.

In an embodiment, the at least one additional active agent is selected from the group consisting of alkylating agents, barbiturates, tubulin binders, corticosteroids, and combinations thereof. In one embodiment, the at least one additional active agent is a therapeutic agent selected from the group consisting of: ibrutinib, rituximab, doxorubicin, prednisolone, vincristine, velcade and evelorimus, and combinations thereof. In one embodiment, the at least one additional active agent is selected from the group consisting of cyclophosphamide, hydroxydonorubicin (also referred to as doxorubicin or Adriamycin ™), vincristine (also referred to as Oncovin ™), prednisone, And a therapeutic agent selected from a combination of these.

In embodiments, the at least one additional active agent is a non-therapeutic agent selected to ameliorate one or more side effects of the apical mode composition. In one embodiment, it is selected from the group consisting of ondansetron, granisetron, dolassitron and palanosetron. In one embodiment, the non-therapeutic agent is selected from the group consisting of finsoleol and risperidone.

In an embodiment, at least one additional agent is a PD-1 / PDL-1 pathway inhibitor. In an embodiment, the PD-1 / PDL-1 pathway inhibitor is selected from the group consisting of Pembrudra, avelumab, atheolizumab (MPDL3280A), nobiludip (BMS-936558), pidilizumab (CT- , MSB0010718C, and MEDI4736.

In embodiments, the at least one additional active agent is selected from the group consisting of inhibitors of the mTOR pathway, TKI inhibitors, PI3K inhibitors, dual PI3K / mTOR inhibitors, SRC inhibitors, VEGF inhibitors, Janus kinase A c-MET inhibitor, a histone deacetylase inhibitor, an anti-mitotic agent, a multi-drug resistance efflux inhibitor, an antibiotic, and a cytokine. In one embodiment, the second therapeutic agent is a therapeutic cytokine. In one embodiment, the second therapeutic agent is interleukin-2. In another embodiment, the second therapeutic agent is selected from a tyrosine kinase inhibitor (e. G., Ebelorimus, bevacizumab).

In an embodiment, the mTOR inhibitor is selected from the group consisting of rapamycin (also referred to as sirolimus), Ebelorimus, Thames rorimus, ridaforolimus, umirolimus, zotarolimus, INK-128, INK128, WYE-132, Torin-1, pyrazolopyrimidine analog PP242, PP30, PP487, PP121, KU0063794, KU-BMCL-200908069-1, Wyeth-BMCL-200910075-9b, INK- XL388, AZD8055, P2281, and P529. Liu et al. Drug Disc. Today Ther. Strateg., 6 (2): 47-55 (2009).

In an embodiment, the mTOR inhibitor is selected from the group consisting of trans-4- [4-amino-5- (7-methoxy-1 H-indol-2- yl) imidazo [5,1- f] [1,2,4] -7-yl] imidazo [5,1-f] [1,2,4] triazolo [3,3- triazin-7-yl] cyclohexane carboxylic acid (also known as OSI-027) and any salts, solvates, hydrates and other physical forms thereof, crystals or amorphous. See US 2007/0112005. OSI-027 can be prepared according to US 2007/0112005, which is incorporated herein by reference. In one embodiment, the mTOR inhibitor is OXA-01. See WO 2013152342 A1.

In embodiments, the PI3K inhibitors may be selected from the group consisting of GS-1101 (Idelalisib), GDC0941 (Pictyisib, Pictilisib), LY294002, BKM120 (Buparilisib, Buparlisib), PI-103, TGX-221, IC-87114, XL PIK-93, PIK-90, AZD6482, IPI-145 (Duvelisib), TG100-115, AS-252424, PIK-147, ZSTK474, BYL719, AS-605240, PIK- PIK294, AS-604850, GSK2636771, BAY 80-6946 (Copanlisib), CH5132799, CAY10505, PIK-293, TG100713, CZC24832 and HS-173.

In an embodiment, the dual PI3K / mTOR inhibitor is selected from the group consisting of GDC-094, WAY-001, WYE-354, WAY-600, WYE-687, Wyeth- BMCL- 200910075-16b, Wyeth- BMCL-200910096-27, KU0063794 and KUBMCL- Selected from the group consisting of GDC-0908069-5, NVP-BEZ235, XL-765, PF-04691502, GDC-0980 (Apitolisib), GSK1059615, PF-05212384, BGT226, PKI-402, VS-558 and GSK2126458 do. Liu et < RTI ID = 0.0 > al., ≪ / RTI > Drug Disc. Today Ther. Strateg., 6 (2): 47-55 (2009).

In embodiments, the mTOR pathway inhibitor is a polypeptide (e. G., An antibody or fragment thereof) or a nucleic acid (e. G., An antibody or fragment thereof) that binds to and inhibits expression levels or activity or a protein (or nucleic acid encoding a protein) Double-stranded small interfering RNA, short hairpin RNA, micro-RNA, antisense oligonucleotides, locked nucleic acid or aptamer). For example, the polypeptide or nucleic acid can be selected from the group consisting of mTOR complex 1 (mTORC1: mTOR Complex 1), mTOR regulatory-related protein (Raptor), mammalian lethal SEC13 protein 8 (MLST8), 40 kDa proline DEP domain-containing mTOR-interacting protein, mTOR complex 2 (mTORC2 complex), and DEP domain-containing mTOR-interacting protein (PRA40: proline-rich Akt substrate of 40 kDa) the rapamycin-insensitive companion of mTOR of mTOR, the G protein beta subunit-like G-L, the mammalian stress-activated protein kinase interaction protein 1 ( Ras-related C3 botulinum toxin substrate 1, mitochondrial stress-activated protein kinase interacting protein 1, paxillin, RhoA, Ras-related C3 botulinum toxin substrate 1, Cdc42 : Cell division control protein 42 ho (eIF4E) -binding protein < RTI ID = 0.0 > (eIF4E) -binding protein < / RTI > (4EBPs) or nucleic acids encoding one of these proteins.

In an embodiment, the SRC inhibitor is selected from the group consisting of bosutinib, saracatinib, dasatinib, ponatinib, KX2-391, XL-228, TG100435 / TG100855 and DCC2036 . See, for example, Puls et al. Oncologist. May 2011; 16 (5): 566-578. In one embodiment, the SRC inhibitor is a polypeptide (e. G., An antibody or fragment thereof) or a nucleic acid (e. G., A double or triple) that binds to a nucleic acid encoding a SRC protein or SRC protein and inhibits its expression level or activity. Stranded small interfering RNA, short hairpin RNA, microRNA, antisense oligonucleotide, lock nucleic acid or aptamer).

In an embodiment, the VEGF inhibitor is selected from bevacizumab, suinitinib, pazopanib, axitinib, sorafenib, regorafenib, lenvatinib and motesanib. In one embodiment, a VEGF inhibitor is a polypeptide (e. G., An antibody or fragment thereof) or a nucleic acid (e. G., An antibody or fragment thereof) that binds to a VEGF protein, a VEGF protein receptor, or a nucleic acid encoding such a protein and inhibits its expression level or activity For example, double-stranded small interfering RNA, short hairpin RNA, micro-RNA, antisense oligonucleotides, morpholino, locked nucleic acids or aptamers). For example, the VEGF inhibitor is a soluble VEGF receptor (e. G., Soluble VEGF-C / D receptor (sVEGFR-3)).

In an embodiment, the JAK inhibitor is selected from the group consisting of facitinib, ruxolitinib, baricitinib, CYT387 (CAS No. 1056634-68-4), lestaurtinib, parkritinib pacritinib) and TG101348 (CAS No. 936091-26-8). In one embodiment, the JAK inhibitor is a polypeptide that binds to a nucleic acid encoding a JAK (e.g., JAK1, JAK2, JAK3 or TYK2) or a JAK protein and inhibits its expression level or activity (e. (E. G., Double-stranded small interfering RNA, short hairpin RNA, microRNA, antisense oligonucleotide, morpholino, lock nucleic acid or aptamer).

In embodiments, the Raf inhibitor is selected from the group consisting of PLX4032 (vmurafenib), sorapenib, PLX-4720, GSK2118436 (dabrafenib), GDC-0879, RAF265, AZ 628, NVP-BHG712, SB90885, ZM 336372, GW5074, TAK-632, CEP-32496 and LGX818 (Encorafenib). In one embodiment, the Raf inhibitor is a polypeptide that binds to a nucleic acid encoding Raf (e.g., A-Raf, B-Raf, C-Raf) or a Raf protein and inhibits its expression level or activity (E. G., Double-stranded small interfering RNA, short hairpin RNA, microRNA, antisense oligonucleotide, morpholino, locked nucleic acid or aptamer). In one embodiment, the MEK inhibitor is selected from the group consisting of AZD6244 (Selumetinib), PD0325901, GSK1120212 (Trametinib), U0126-EtOH, PD184352, RDEA119 (Rafametinib), PD98059, BIX (Bimetinib), AS-703026 (Pimasertib), SL-327, BIX02188, AZD8330, TAK-733 and PD318088. In one embodiment, the MEK inhibitor is a polypeptide that binds to a nucleic acid encoding MEK (e.g., MEK-1, MEK-2) or a MEK protein and inhibits its expression level or activity (e. (E. G., Double-stranded small interfering RNA, short hairpin RNA, microRNA, antisense oligonucleotide, morpholino, lock nucleic acid or aptamer).

In embodiments, the Akt inhibitor is selected from the group consisting of MK-2206, KRX-0401 (perifosine), GSK690693, GDC-0068 (Ipatasertib), AZD5363, CCT128930, A-674563, PHT-427 Is selected. In one embodiment, the Akt inhibitor is a polypeptide that binds to a nucleic acid encoding an Akt (e.g., Akt-1, Akt-2, Akt-3) or Akt protein and inhibits its expression level or activity (E. G., Double-stranded small interfering RNA, short hairpin RNA, microRNA, antisense oligonucleotide, morpholino, locked nucleic acid or aptamer).

In an embodiment, the farnesyl transferase inhibitor is selected from LB42708 or tipifarnib. In one embodiment, the parnesyltransferase inhibitor is a polypeptide (e. G., An antibody or fragment thereof) that binds to a nucleic acid encoding a parnesyltransferase or parnesyltransferase protein and inhibits its expression level or activity, Or a nucleic acid (e.g., double-stranded small interfering RNA, short hairpin RNA, microRNA, antisense oligonucleotide, morpholino, lock nucleic acid or aptamer).

In one embodiment, the c-MET inhibitor is selected from crizotinib, tivantinib, cabozantinib, foretinib. In one embodiment, the c-MET inhibitor binds to a nucleic acid encoding a c-MET protein or HGF ligand, such as c-MET or ficlatuzumab or rilotumumab, and its expression level or activity (E. G., Antibodies or fragments thereof) or nucleic acids (e. G., Double-stranded small interfering RNA, short hairpin RNA, microRNA, antisense oligonucleotides, morpholino, )to be.

In one embodiment, the histone modulation inhibitor is selected from the group consisting of anacardic acid, C646, MG149 (histone acetyltransferase), GSK J4 Hcl (histone dimethylanase), GSK343 (active against EZH2), BIX 01294 Methyltransferase), MK0683 (Vorinostat), MS275 (Entinostat), LBH589 (Panobinostat), Trichostatin A, MGCD0103 (Mosetinostat Mocetinostat), Tasquinimod, TMP269, Nexturastat A, RG2833, PDX101 (Belinostat).

In an embodiment, the anti-mitotic agent is selected from the group consisting of Griseofulvin, vinorelbine tartrate, paclitaxel, docetaxel, vincristine, vinblastine, Epothilone A, epothilone B, ABT- 751, CYT997 (Lexibulin), Binflunine tartaric acid, Fosbretabulin, GSK461364, ON-01910 (Rigosertib), Ro3280, BI2536, NMS-P937, BI 6727 Volasertib), HMN-214 and MLN0905.

In embodiments, the tyrosine kinase inhibitor is selected from the group consisting of Votrient, Axitinib, Bortezomib, Conservatib, Carfilzomib, Crizotinib, Dabbaffenib, Dasatinib, A combination of Erlotinib, Gefitinib, Iblatinib, Imatinib, Lapatinib, Nilotinib, Pegaptanib, Ponatinib, LEGO, Is selected from the group consisting of Regorafenib, Ruxolitinib, Sorapenib, Suminitinib, Trametinib, Vandetanib, Vemurafenib and Vismodegib.

In one embodiment, the polyether antibiotic is selected from sodium monensin, nigericin, valinomycin, salinomycin.

A " pharmaceutical composition " is a formulation containing a compound according to the invention in a pharmaceutically acceptable form suitable for administration to a subject. As used herein, the phrase " pharmaceutically acceptable ", within the scope of sound medical judgment, is intended to encompass humans and animals, such as humans and animals, to a reasonable benefit / risk ratio, without undue toxicity, irritation, allergic response, Refers to a compound, substance, composition, carrier and / or dosage form suitable for use in contact with the tissue of the subject.

&Quot; Pharmaceutically acceptable excipient " means an excipient that is generally safe, non-toxic, biologically or otherwise useful in the manufacture of a desired pharmaceutical composition, and is intended for use as a human, Including possible excipients. Examples of pharmaceutically acceptable excipients include, but are not limited to, sterile liquids, water, buffered physiological saline, ethanol, polyols such as glycerol, propylene glycol, liquid propylene glycol and the like, oils, surfactants, excipients, carbohydrates But are not limited to, glucose, lactose, sucrose or dextran), antibiotics (such as ascorbic acid or glutathione), chelating agents, low molecular weight proteins or suitable mixtures thereof.

The pharmaceutical composition may be provided in the form of a volume or dosage unit. It is particularly advantageous to formulate pharmaceutical compositions in dosage unit form for ease of administration and consistency of dosage. As used herein, the term " dosage unit form " refers to physically discrete units suitable as a single dosage unit for the individual to be treated; Each unit containing a predetermined amount of active compound was calculated to produce the desired therapeutic effect associated with the required pharmaceutical carrier. The specifications for the dosage unit form of the invention are determined by the unique characteristics of the active compound and the particular therapeutic effect achieved and are directly dependent. The single dosage form may be a single pump on an ampoule, vial, suppository, dragee, tablet, capsule, IV bag or aerosol inhaler.

In therapeutic applications, the dosage will vary depending upon the nature of the formulation, the age, weight and clinical condition of the recipient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors that affect the selected dosage. Generally, the dose should be a pharmaceutically effective amount. Dosages can be given in mg / kg / day of measurement (dose can be adjusted for kg of patient's weight, m ² of body surface area and year of age). An effective amount of the pharmaceutical composition is to provide an objectively identifiable improvement, as noted by the clinician or other qualified observer. For example, relieving the symptoms of a disease, disorder or condition. As used herein, the term " effective method of administration " refers to the amount of a pharmaceutical composition to produce a desired biological effect in a subject or cell.

For example, the dosage unit form may be from 1 nanogram to 2 milligrams, or from 0.1 milligrams to 2 grams; 10 milligrams to 1 gram, or 50 milligrams to 500 milligrams or 1 microgram to 20 milligrams; From 1 microgram to 10 milligrams; Or from 0.1 milligram to 2 milligrams.

The pharmaceutical composition may be administered by any suitable route, including, but not limited to, pulmonary, inhalation, nasal, oral, buccal, sublingual, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, intrapleural, (For example, liquid, aerosol, solution, inhalant, mist, spray, or solid, powder, ointment, paste, cream, lotion) for administration by a transdermal, transdermal, transmucosal, rectal, , Gel, patch, etc.). For example, the pharmaceutical composition of the present invention may be in the form of an aqueous solution or powder for aerosol administration by inhalation or insufflation (mouth or nose), in the form of a tablet or capsule for oral administration; In the form of sterile aqueous solutions or dispersions suitable for administration by addition of a sterile injectable solution for direct injection or intravenous infusion; Creams, foams, patches, suspensions, solutions or suppositories for transdermal or intramuscular administration.

Pharmaceutical compositions include, but are not limited to, capsules, tablets, buccal forms, troches, lozenges and oral liquid in the form of emulsions, aqueous suspensions, dispersions or solutions. Or < / RTI > an orally acceptable dosage form. Capsules may contain inert fillers and / or diluents such as powdered cellulose such as pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweeteners, crystalline and microcrystalline cellulose, flour, gelatin, ≪ / RTI > of a compound of the invention. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants such as magnesium stearate may also be added. In the case of capsules, the diluents useful for oral administration include lactose and dried corn starch. When aqueous suspensions and / or emulsions are administered orally, the compounds of the present invention may be suspended or dissolved in the oil and may be combined with emulsifying and / or suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added.

The pharmaceutical composition may be in the form of a tablet. The tablet may comprise a single dosage form of the compound of the invention together with an inert diluent or carrier such as, for example, lactose, sucrose, sorbitol or mannitol, such as sugars or sugar alcohols. The tablet may further comprise a non-saccharide-derived diluent, such as sodium carbonate, calcium phosphate, calcium carbonate or cellulose, or derivatives thereof such as methylcellulose, ethylcellulose, hydroxypropylmethylcellulose and starches such as corn starch . Tablets may be prepared by dissolving or dispersing the active ingredient in a solvent such as polyvinylpyrrolidone, a disintegrant (e.g., a cross-linked polymer having swellability such as cross-linked carboxyl methylcellulose), a lubricant (e. G., Stearate) Such as, for example, parabens), antioxidants (e.g., BHT), buffering agents (e.g., phosphate or citrate buffers), citrate / bicarbonate mixtures, and effervescent agents can do.

The tablet may be a coated tablet. The coating may be applied to control the release of the protective film coating (e. G., Wax or varnish) or the active agent, e. G., To release the release of the active agent after a predetermined delay time after ingestion, Coating. The latter can be achieved, for example, by using a coating, such as an enteric film coating sold under the brand name Eudragit (R).

Tablet formulations may be produced by conventional compression, wet granulation or dry granulation methods and may be prepared by conventional means including, but not limited to, magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, calcium carboxylmethylcellulose, Sodium citrate, complex silicate, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, But are not limited to, pharmaceutically acceptable diluents, binders, lubricants, disintegrants, surface modifying agents (including surfactants), suspending agents or stabilizers, including, but not limited to, starches, Can be used. Preferred surface modifiers include both anionic and anionic surface modifiers. Representative examples of surface modifying agents include poloxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, Phosphate, sodium dodecyl sulfate, magnesium aluminum, silicates, and triethanolamine.

The pharmaceutical composition may be in the form of a hard or soft gelatin capsule. According to this formulation, the compounds of the present invention may be in solid, semi-solid or liquid form.

The pharmaceutical composition may be in the form of a sterile aqueous solution or dispersion suitable for parenteral administration. The term " parenteral ", as used herein, refers to any subcutaneous, intradermal, intravenous, intramuscular, intraarticular, intrathecal, intrasynovial, intrasternal, intraspinal, intralesional, , Intracranial injection or infusion techniques.

The pharmaceutical composition may be in the form of a sterile aqueous solution or dispersion suitable for administration by addition to a sterile injectable solution for direct injection or intravenous infusion, and may contain water, ethanol, a polyol such as glycerol, propylene glycol and liquid polyethylene glycol ), Mixtures thereof, or a solvent or dispersant medium containing one or more vegetable oils. A solution or suspension of a compound of the invention, such as a free base or a pharmaceutically acceptable salt, may be prepared in water suitably mixed with a suspension. Examples of suitable suspensions are given below. Dispersing agents may also be prepared, for example, in glycerol, liquid polyethylene glycols and mixtures thereof in oils.

Pharmaceutical compositions for use in the methods of the invention may further comprise one or more additives that are added to any carrier or diluent (such as lactose or mannitol) presented in the formulation. The one or more additives may comprise or consist of one or more suspensions. The suspension generally has a long aliphatic chain, such as one or more fatty acids, that allows it to be inserted directly into the lipid structure of the cell, which increases drug penetration and absorption. The empirical parameter commonly used to express the relative hydrophilicity and hydrophobicity of the suspension is the hydrophilic-lipophilic balance (" HLB " value). Suspensions with lower HLB values are more hydrophobic and have better solubility in oils, while suspensions with higher HLB values are more hydrophilic and have better solubility in aqueous solutions. Thus, a hydrophilic suspension is generally regarded as a compound having an HLB value of at least about 10, and a hydrophobic suspension is regarded as a compound having an HLB value of less than about 10. However, since for many suspensions the HLB value may differ by about 8 HLB units, this HLB value is only a guideline.

Suspensions for use in the compounds of the present invention include polyethylene glycol (PEG) -fatty acids and PEG-fatty acid mono and diesters, PET glycerol esters, alcohol-oil ester transesterification products, polyglyceryl fatty acids, propylene glycol fatty acid esters , Polyethylene glycol alkyl esters, sugars and derivatives thereof, polyethylene glycol alkyl phenols, polyoxyethylenepolyoxypropylene (POE-POP) block copolymers, sorbitan fatty acid esters, anion suspensions, fat soluble vitamins and their salts , Aliphatic derivatives of water-soluble vitamins, amino acids and salts thereof, organic acids and their esters and anhydrides.

The present invention also provides a packaging and kit comprising a pharmaceutical composition for use in the methods of the present invention. The kit may comprise one or more containers selected from the group consisting of bottles, vials, ampoules, blister packs and syringes. The kit may comprise one or more instructions for use in the treatment and / or prevention of a disease, condition or disease of the invention, one or more syringes, one or more applicators or sterilization suitable for reconstituting the pharmaceutical compositions of the invention Solution. ≪ / RTI >

All percentages and ratios used in the present invention are by weight unless otherwise specified. Other features or advantages of the invention will be apparent from the different embodiments. The examples provided illustrate various components and methods useful in practicing the invention. The examples do not limit the claims of the present invention. Based on the present invention, one skilled in the art can ascertain and utilize other components and methods useful in practicing the invention.

Example

Example  One: TFEB In Aphelly mode  .

Aplylmode has previously been shown to be highly cytotoxic in TSC null cells. In these cells, the mTOR pathway is constantly active, as in many cancers. Screening of more than 100 cancer cell lines showed that Aplymido was cytotoxic in various types of cancer. These results further indicate that the cytotoxic activity of aplylide mode is due to inhibition of intracellular exchange and corresponds to an increase in apoptosis and / or autophagy.

To better understand the cellular mechanism of action of the apical mode, the overall effect of the changes following the Aphelly mode treatment of two non-Hodgkin's B cell lymphoma (B-NHL) tumor cell lines, SU-DHL-10 and WSU-DLCL2 Global gene expression analysis was performed. Figure 1 shows a heatmap representation of gene expression changes. Up-regulated genes are denoted in red and dense toward the top of the heatmap, while down-regulated genes are denoted in blue and dense downward. Next, a gene ontology analysis was performed. As shown in Figure 2, there was a pronounced concentration of the lysosomal gene induced by the aplyly mode. Next, LysoTracker staining was used to observe the acidified compartment of the cells. Figure 3 shows that there was an expansion of the acidified compartment, which implies that lysosomal biosynthesis is up-regulated by the apical mode, just like gene expression results.

TFEB is a major regulator of lysosomal gene expression and is activated by dephosphorylation following nuclear translocation (Roczniak-Ferguson et al., 2012; Settembre et al., 2012). Thus, the TFEB phosphorylation state and subcellular localization after the Apillia mode treatment were next observed. Figure 4 shows that within 2 hours of treatment, TFEB is dephosphorylated (by increased electrophoretic mobility) and migrates into the nucleus (Wang et al., 2015), as observed in other cell types. Overall, these results indicate that after increased lysosomal gene expression, Apelli mode induces TFEB dephosphorylation and nuclear translocation.

To further study the role of TFEB in cell responses to aplylmode, expression levels of TFEB were extracted through other cancer cell lines from the Cancer Cell Line Encyclopedia (CCLE) database, and TFEB expression and Apillis To determine if there is a correlation between the sensitivity of the cell line to the mode. Figure 5 shows the expression levels of TFEB in a number of cell lines. As shown in Figure 5, TFEB is highly expressed in B-NHL compared to all other tumor types. TFEB was overexpressed in the TFEB-deficient B-NHL cell line CA46 to test whether increased TFEB expression contributed to the observed apilly-mode susceptibility in B-NHL. As shown in Fig. 6, TFEB overexpression increased the sensitivity of Aphellymode to over 50-fold.

In conclusion, the data presented in the present invention demonstrate that high levels of TFEB expression have susceptibility to Apilly Modes.

Example  2: in cancer Microanesthesia ( MiT ) Transcription factor

TFEB is a member of the MiT family of basic helical-loop-helix leucine zipper transcripts (Fisher et al. 1991), which also includes the highly homologous genes MITF, TFE3 and TFEC. MITF is the most well-characterized, melanoma and clear cell sarcoma of this line, as well as an established driver, as well as a major regulator of melanocyte biosynthesis (Steingrimsson et al. 2004; Garraway et al. 2005; Davis et al., 2006). Overexpression of TFEB and TFE3 through chromosomal translocation is associated with renal cell carcinogenesis, and TFE3 overexpression is also associated with soft tissue sarcoma and perivascular mesangial cell tumors (Haq et al. 2011; reviewed in Kauffman et al. 2014). TFEC expression is restricted to macrophages and is the least studied MiT family member with little known function (Rehli et al. 1999). Members of the MiT family are known to regulate endolysomes and autophagosome biosynthesis as well as autophagy, and TFEB is particularly referred to as the main modulator of lysosomes (Sardiello et al. 2009; Settembre et al. 2012; Martina et al., 2014, Ploper et al., 2015). Considering that high levels of TFEB have susceptibility to Apilly Modes in B-NHL, other cancers characterized by increased expression and / or activity of one or more MiT family of transcription factors may also be susceptible . These may include, but are not limited to, renal cell carcinoma, melanoma, clear cell sarcoma, salivary soft tissue sarcoma, and perivascular mesangial cell tumor.

Example  3: kidney cells carcinoma

TFEB, TFE3 and MITF, along with other genes that are frequently mutated in renal cell carcinomas (RCCs), such as VHL, MET, FLCN, fumarate hydratase, succinate dihydrogenase, TSC1 and TSC2, By altering the metabolism, each was associated with kidney cancer (Linehan 2012). TFEB and TFE3 translocation due to overexpression of functional transcription factors and nuclear localization occurs in rare RCC subtypes, translocation carcinomas corresponding to 1-5% of sporadic RCCs (Shuch et al. 2015 ). In addition, a novel oncogenic MITF fusion gene, ACTG1-MITF, has been identified as RCC (Durinck et al, 2015). As a result, germline missense mutations of MITF due to increased transcriptional activity have been reported in both melanomas and RCCs (Bertolotto et al. 2011).

RCCs are the most common type of kidney cancer in adults, accounting for 2-3% of adult malignancies and 90-95% of kidney-developing tumors (Cancer Facts and Figures 2015). Each year there are about 65,000 new cases of RCC in the United States, about 13,500 deaths due to RCC each year, and a median age of disease age 65 (Siegel et al. 2012). Progressive RCCs are associated with targeted therapies including VEGF inhibitors (suinitinib, pazopanib, bevacizumab, sorafenib, carbojantinib, and axitinib) and mTOR inhibitors (eberolimus and temiculolimus) It is treated with nephrectomy (Cancer Facts and Figures 2015).

Transparent RCC is a predominant histologic subtype of RCC that accounts for about 75% of all RCCs (Shuch et al. 2015). These tumors are known for their abundant clear cytoplasm due to lipid and glycogen deposits (Shuch et al. 2015). Transparent RCCs tend to appear as metastatic disease of a higher grade, poor prognosis (Shuch et al. 2015). Variations in the von Hippel-Lindau gene VHL are reported to occur up to 90% of the clear cell RCC (Nickerson et al. 2008). Deviations in VHL function as ubiquitin ligase may result in upregulation of the hypoxia-responsive gene including accumulation of transcription factor HIF-alpha and VEGF and PDGF and subsequent signaling such as RAF-MEK-ERK and PI3K-Akt-mTOR (Clarke 2009).

Next, many clear cell RCCs cell lines demonstrated susceptibility to in vitro Apillia mode with a sensitivity defined as an EC50 of less than 200 nM in a five day assay (FIG. 7 and Table 1, below). Aphellymode also showed excellent activity against clear cell RCCs as compared to the standard of care treatment in a five day analysis, axitinib, sorafenib, pazopanib, sunitii and rapamycin ( 8).

The mean EC50 value from ten clear cell RCC strains tested in the five-day analysis in Apillia mode Cell line EC50 (nM)
(Average, n = 2) 769-P 44 RCC-MF 8 RCC-ER 9 RCC-FG2 32 RCC-JF 60 786-0 71 A-704 11 RCC-JW 27 KMRC-1 4 KMRC-3 39

As shown in Table 2, the data also suggest that Apelli mode is preferentially cytotoxic in RCC with VHL mutation.

The mean EC50 value and VHL status from the RCC corpuscles, Cell line EC50 (nM)
(Average, n = 2) VHL  condition Caki-1 2276 WT ACHN 9039 WT 769-P 44 Mutant RCC-ER 9 Mutant RCC-FG2 32 Mutant RCC-JF 60 Mutant 786-0 71 Mutant A-704 11 Mutant KMRC-1 4 Mutant KMRC-3 39 Mutant Caki-2 3355 Mutant A498 84009 Mutant

Considering that the clear cell RCCs exhibit cytotoxicity to apical mode, it is preferable that the papillary phase type I or type II, non-staining cells of the anterior pituitary gland, a hybrid, an eosinophilic granulosa cell, a translocation, a blood vessel muscle lipidoma, Other RCC subtypes, including but not limited to, collecting neoplasia, are also suggested to be susceptible to Apelli mode.

Example  4: TFEB Translocation  Kidney cell carcinoma

TFEB translocated RCCs are rare, and so far, approximately 50 cases have been reported (Argani 2015). This figure may be less than the actual number due to misdiagnosis due to lack of established clinical characteristics. Out of 50 cases, there were four cases of metastases and three of these cases died (Argani, 2015). The median age of onset of TFEB translocation RCCs is 31 years, and early childhood cytotoxic chemotherapy is associated with a causal subset of cases (Argani, 2015).

TFEB translocated RCCs have a specific t (6; 11) (p21; q12) translocation that fuses the TFEB locus to an untranslated functional, alpha (MALAT1) of unknown function due to overexpression of full- 2003; Kuiper et al., 2003; reviewed in Kauffman et al. The alpha-TFEB fusion gene can be detected by RT-PCR, DNA PCR or FISH (Argani et al. 2005; Argani et al. 2012). In addition, the CLCTC-TFEB fusion gene has recently been identified in translocated RCC tumors, which are expected to function similarly to the alpha-TFEB fusion gene (Durinck et al., 2015). TFEB translocated RCCs are represented by qRT-PCR 30-60 fold upregulation of TFEB transcription, and this result is associated with a high expression of TFEB protein (Kuiper et al., 2002), as compared to normal kidney tissue, as assessed by Western blot. 2003) and strong nuclear TFEB staining (Argani et al. 2005), as detected by IHC.

Clinically, TFEB translocated RCCs do not have distinct appearance and can be given a broad differential diagnosis of high-grade unclassified RCC (Argani, 2015). However, these tumors demonstrate nuclear TFEB immunoreactivity by IHC and also stain positively for melanoma markers Melan A and HMB45, along with cysteine protease cathepsin K (Argani et al. 2005; Martignoni et al. 2009 ). Since TFEB breakapart FISH analysis is less affected by various immobilisations, this is the preferred diagnostic test for TFEB translocated RCC in formalin-fixed and paraffin-embedded materials (Argani et al. 2012).

Although the clinical relevance of TFEB translocated RCC has been established, there is currently no effective remedy for advanced translocation RCC. Given that high levels of TFEB have proved to be susceptible to Apillia mode in B-NHL, this assumption has the hypothesis that TFEB translocated RCCs will also exhibit a sensitive sensitivity to Aphelly mode.

Example  5: TFE3 Translocation  Kidney cell carcinoma

TFE3 translocation RCCs, accounting for 40% of pediatric RCCs and less than 5% of adult RCCs, have approximately 10 new pediatric and 1,260 new adult cases each year in the United States (Magers et al. As with TFEB translocated RCCs, early cytotoxic chemotherapy is implicated as a cause of TFE3 translocation RCC that tends to occur 2-14 years after exposure. Although the childhood case of TFE3 RCC tends to be indolent, adult cases are frequently associated with early nodal-related, positive metastasis and a similar prognosis to clear cell RCC (Magers et al., 2015, Geller et al., 2008). In addition, these tumors may reappear after decades of complete metastatic tumors decades ago (Dal Cin P et al, 1998; Rais-Bhahrami S, et al, 2007).

Clinically, TFE3 translocation RCCs are similar to clear cell RCCs with papillary structures and epithelial clear cells. Morphology can vary to be similar to other RCC subtypes, making classification difficult (Argani, 2015). With respect to pertinence, these tumors exhibit strong nuclear TFE3 immunoreactivity, also stained positively for CD10 and RCC antigens, and frequently positively stained for cathepsin K (Argani et al. 2003; Argani et al., 2005; Martignoni et al., 2009).

Five types of translocations related to the TFE3 locus on Xp11 have been documented to date: PRCC-TFE3, ASPSCR1-TFE3, SFPQ-TFE3, NONO-TFE3 and CLTC-TFE3 (Kauffman et al. The PRCC-TFE3, ASPSCR1-TFE3 and SFPQ-TFE3 translocations have been identified as recurrent mutations identified in multiple patients while the NONO-TFE3 and CLTC-TFE3 fusion genes have been identified as single patient) (Kauffman et al. 2014). In particular, the ASPSCR1-TFE3 fusion gene has also been identified as a recurrent mutation in a rare lung cancer type, soft tissue sarcoma, and the SFPQ-TFE3 fusion gene has been identified in the periampullary adenocarcinoma tumor (Landanyi et al. 2001; Tanaka et al. ). The breakpoint position of these fusion genes varies but becomes a fusion product with the N-terminal portion of each fusion partner linked to the C-terminal TFE3 exon region. All fusion partners have over-expression of functional TFE3 protein with a continuously active promoter (Kauffman et al. 2014). The TFE3 translocation can be detected by strong nuclear staining (Argani 2015) by antibody corresponding to the TFE3 C-terminus or by break-through FISH analysis.

Some cell lines were derived from TFE3 translocated RCCs; The PRCC - TFE3 fusion gene is found in cell lines UOK120, UOK124 and UOK146; The SFPQ - TFE3 fusion gene appears in the UOK145 cell line; The ASPSCR1 - TFE3 fusion gene appears in the FU-UR1 cell line; The NONO- TFE3 fusion gene appears in the UOK109 cell line (Kauffman et al. 2014).

TFE3 translocation cell lines, including, but not limited to, TFE3 translocation RCCs, salivary gland sarcoma and perivascular mesangial cell tumors are also believed to exhibit susceptibility to Apilly Modes.

Reward sarcoma

Leiomyosarcoma (ASPS) is a rare, slow-growing neoplasm of unknown origin. The ASPS appears less than 1% of the 12,000 new cases of soft tissue sarcoma diagnosed each year in the United States (Jaber and Kirby 2014; National Cancer Institute 2014), adult thighs or buttocks, And the soft tissues of the neck (Jaber and Kirby 2014). Metastasis to lung, bone, brain and / or liver occurs in up to 79% of patients (Lieberman et al. 1989; Portera et al. 2001). Metastatic ASPS is generally resistant to conventional radiotherapy and chemotherapy (Jaber and Kirby 2014).

ASPS is characterized by a specific translocation der (17) t (X; 17) (p11; 25), in which TFE3 is fused to ASPSCR1, resulting in overexpression and nuclear localization of functional TFE3 (Jaber and Kirby 2014 ). The cells in the tumor were incubated with cells containing a specific organoid, periodic acid-Schiff, a reward-like pattern of growth, a distase-resistant intracytoplasmic crystal (Jaber and Kirby 2014). Tumors are consistently positive for strongly nuclear TFE3 staining by IHC as well as for cathepsin K. To date, only one cell line, cell line ASPS-1, has been derived from ASPS tumors (Kenney et al. 2011).

Given that TFEB overexpression is sensitive to the Apillia mode, cancer and cell lines, including but not limited to ASPS and cell line ASPS-1, including overexpression of other MITF family members such as TFE3, Lt; / RTI >

Burt - Hog - Dube  syndrome( Birt - Hogg - Dube  Syndrome)

The Burt's Hog Doubles (BHD) syndrome is an autosomal chromosome that originates from a mutation (17p11.2) on chromosome 17 in the policulin (FLCN) gene, the only known susceptibility gene for BHD (Schmidt et al, 2005) (Birt et al., 1977). FLCN BHD mutations vary in 53 distinct germ cell mutations identified (Wei et al. 2009). Patients with BHD become vulnerable to a variety of proliferative disorders, including follicular hamartoma, lung cysts and kidney tumors (BHDsyndrome.org).

Mechanically, FLCN complexes with policulin-interacting protein-1 (FNIP1) and -2 (FNIP2) and 5'-AMP-activated protein kinase (AMPK) were formed and ligated to the regulation of mTOR, Linked to the regulation of proliferation (Baba et al 2010). In addition, FLCN was found to negatively regulate TFE3 nuclear localization by regulating FLCN expression in the clear-cell kidney tumor cell line, UOK257 cells from BHD patients with mutated FLCN (Yang et al.) (Hong et al 2010 ). Consistent with these results, FLCN-depleted ARPE-19 cells showed TFE3 nuclear accumulation (Martina et al. 2014). Analysis of the UOK257 xenograft showed a tumor staining positively for nuclear TFE3, whereas normal adjacent kidney tissues showed weak cytoplasmic staining. To further confirm these results, Flcn-null MEFS showed localized TFE3 in the nucleus. As a result, IHC staining showed nuclear or nuclear / cytoplasmic staining in tumor samples from BHD patients. To confirm that FLCN inactivation increased TFE3 transcriptional activity, TFE3-targeted GPNMB was used as a surrogate marker and increased in tumors from BHD patients compared to normal kidney tissue by Western blot analysis . IHC also demonstrated GPNMB expression in tumors and Flcn +/- heterozygote mouse kidney tumors that are not normal tissue in sections from BHD patients (Hong et al 2010). Overall, these results link functional inactivation of FLCN with increased nuclear TFE3 localization and transcriptional activity, as observed in patients with BHD.

Considering the assumption that aplylmode would be effective in tumors with high levels of nuclear TFE3, there were no significant differences between patients with renal (Paulovich et al 2002), colorectal (Kahnoski et al 2003), endometrial (Fujii et al 2006) (Jiang et < RTI ID = 0.0 > al., ≪ / RTI > 2007), but are not limited to those with mutations in Flcn.

Claims (41)

A composition for treating cancer in a subject having cancer cells that overexpress a microphthalmia transcription factor, comprising a therapeutically effective amount of apilimod or a pharmaceutically acceptable salt thereof. 2. The composition of claim 1, wherein the affilient mode is apilimod dimesylate. 3. The composition according to claim 1 or 2, wherein the MiT transcription factor is selected from the group consisting of TFEB, TFE3, TFEC and MITF. 4. The composition of claim 3, wherein the MiT transcription factor is TFEB or TFE3. 5. The method of claim 3 or 4, wherein the cancer is a non-Hodgkins B cell lymphoma, a renal cell carcinoma, a melanoma, a thyroid carcinoma, A clear cell sarcoma, an alveolar soft part sarcoma, or a perivascular epitheloid cell tumor. 6. The composition of claim 5, wherein the cancer is renal cell carcinoma. 7. The composition of claim 6, wherein said kidney cell carcinoma contains a TFEB translocation. 8. The composition of claim 7, wherein the TFEB translocation is a t (6; 11) (p21; q12) translocation. 9. The method of claim 6, 7, or 8, wherein the renal cell carcinoma is selected from the group consisting of papillary type I or type II, chromophobe, hybrids, oncocytoma, Wherein the composition is selected from the group consisting of translocations, angiomyolipomas, oncocytic, medullary and collecting duct carcinomas. 9. The method of claim 6, 7, or 8, wherein the renal cell carcinoma is selected from the group consisting of clear cell type renal cell carcinoma, transitional cell carcinoma, Wilms tumor (nephroblastoma) Wherein the composition is selected from renal sarcoma and benign (non-carcinomatous) renal tumors, renal adenoma, oncocytoma, and angiomyolipomas. 7. The composition of claim 6, wherein said kidney cancer has a mutation in von Hippel-Lindau (VHL) gene. 12. The composition according to any one of claims 1 to 11, further comprising at least one additional active agent. 13. The composition of claim 12, wherein said at least one additional active agent is a therapeutic or non-therapeutic agent, or a combination of therapeutic agent and non-therapeutic agent. 14. The method of claim 13, wherein the at least one additional active agent is selected from the group consisting of a protein kinase inhibitor, a PD-1 / PDL-1 pathway inhibitor, a checkpoint inhibitor, a platinum based anti-neoplastic agent, A nucleoside metabolic inhibitor, an alkylating agent, an intercalating agent, a tubulin binding agent, and combinations thereof. ≪ Desc / Clms Page number 13 > 15. The composition of claim 14, wherein the therapeutic agent is a vascular endothelial cell growth factor (VEGF) inhibitor. 16. The method of claim 15, wherein the VEGF inhibitor is selected from the group consisting of sunitinib, pazopanib, bevacizumab, sorafenib, cabozantinb, and axitinib. ≪ / RTI > 15. The composition of claim 14, wherein the therapeutic agent is an mTOR inhibitor. 18. The composition of claim 17, wherein the mTOR inhibitor is everolimus or temsirolimus. 15. The composition of claim 14, wherein the therapeutic agent is a protein kinase inhibitor. 20. The composition of claim 19, wherein the protein kinase inhibitor is pazopanib or sorafenib, or a combination thereof. 15. The composition of claim 14, wherein said therapeutic agent is a PD-1 / PLD-1 pathway inhibitor. 15. The method of claim 14, wherein the therapeutic agent is selected from the group consisting of pembrolizumab (Keytruda), avelumab, atezolizumab (MPDL3280A), nivolumab (BMS-936558), pidilizumab -011), MSB0010718C and MEDI4736. 23. The composition of any one of claims 1 to 22, further comprising a non-therapeutic agent selected to ameliorate one or more adverse effects of the affix mode. 14. The composition of claim 13, wherein the at least one additional active agent is a non-therapeutic agent. 25. The method of claim 23 or 24, wherein the non-therapeutic agent is selected from the group consisting of ondanestron, granisetron, dolsetron, and palonosetron. Composition. 25. The composition of claim 23 or 24, wherein the non-therapeutic agent is selected from the group consisting of pindolol and risperidone. 27. The composition according to any one of claims 1 to 26, wherein said composition comprises an amount of an apical mode dimesylate effective to inhibit PILfyve kinase activity in a cancer cell of an individual. 28. The composition according to any one of claims 1 to 27, wherein the cancer is refractory or metastatic to standard therapies. 18. The composition according to any one of claims 1 to 17, wherein the composition is in a form suitable for oral or intravenous administration. Comprising administering to a subject a therapeutically effective amount of a composition comprising Apillia mode or a pharmaceutically acceptable salt thereof in a subject having cancer cells that overexpress at least one ocular microtia (MiT) transcription factor. ≪ / RTI > 31. The method of claim 30, further comprising a pretreatment step of analyzing a sample of cancer cells for overexpression of one or more MiT transcription factors. 32. The method of claim 31, wherein said analyzing step comprises the detection of one or more of TFEB, TFE3, TFEC and MITF. 33. The method of claim 32, wherein the analyzing step comprises the detection of TFEB or TFE3. 33. The method of claim 32, wherein said analyzing step is performed using immunohistochemistry. 35. The method of any one of claims 30-34, wherein the affilient mode is an affilient mode dimesylate. 36. The method of claim 35, wherein the therapeutically effective amount of the affirmative mode is an amount effective to inhibit PIKfyve kinase activity in the cancer cells of an individual. A method for inhibiting the proliferation of cancer cells comprising contacting cancer cells with an amount of an affila mode effective to inhibit cell proliferation or a pharmaceutically acceptable salt thereof. A method for inhibiting the survival of cancer cells, comprising contacting cancer cells with an amount of an affinity mode or pharmaceutically acceptable salt thereof effective to inhibit PIKfyve kinase activity in cancer cells. 39. The method of claim 37 or 38, wherein said cancer cells overexpress MiT transcription factors. 40. The method of claim 39, wherein the MiT transcription factor is selected from TFEB, TFE3, TFEC, and MITF. 41. The method of claim 40, wherein the MiT transcription factor is TFEB or TFE3.

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